Tromethamine organocatalyzed efficient tandem-multicomponent synthesis of new thiazolyl-4-thiazolidinones in aqueous medium

Article abstract of DOI:10.1080/00397911.2019.1597124

The catalytic potential of tris(hydroxymethyl)aminomethane (Tromethamine) has been assessed for the one pot three component tandem reaction involving a thiazolylmethoxy phenyl/aromatic carboxaldehyde, substituted amines and thioglycolic acid to form new t

Full text of DOI:10.1080/00397911.2019.1597124

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Tromethamine organocatalyzed efficient tandem-
multicomponent synthesis of new thiazolyl-4-
thiazolidinones in aqueous medium
Manisha R. Bhosle, Sayali A. Kharote, Giribala M. Bondle & Jyotirling R. Mali
To cite this article: Manisha R. Bhosle, Sayali A. Kharote, Giribala M. Bondle & Jyotirling
R. Mali (2019): Tromethamine organocatalyzed efficient tandem-multicomponent synthesis
of new thiazolyl-4-thiazolidinones in aqueous medium, Synthetic Communications, DOI:
10.1080/00397911.2019.1597124
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https://doi.org/10.1080/00397911.2019.1597124
Tromethamine organocatalyzed efficient
tandem-multicomponent synthesis of new
thiazolyl-4-thiazolidinones in aqueous medium
Manisha R. Bhoslea, Sayali A. Kharotea, Giribala M. Bondlea, and Jyotirling
R. Malib
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra,
b
431004, India; College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 26 December 2018
The catalytic potential of tris(hydroxymethyl)aminomethane
(Tromethamine) has been assessed for the one pot three component
tandem reaction involving a thiazolylmethoxy phenyl/aromatic car-
boxaldehyde, substituted amines and thioglycolic acid to form new
thiazolyl-4-thiazolidinones and known substituted-4-thiazolidinones.
This strategy involves the use of tromethamine as a reusable pro-
moter and water as an eco-friendly reaction medium. The merits of
this protocol are high atom economy, mild reaction conditions,
good yields of desired products in short reaction times, and reusable
reaction medium. The generality and functional tolerance of this
convergent and environmentally benign method is demonstrated.
KEYWORDS
4-Thiazolidinone; multicom-
ponent; organocatalysis;
tromethamine
GRAPHICAL ABSTRACT
Introduction
Functionalized thiazolidinones are one of the most extensively investigated class of com-
pounds because of their broad range of pharmacological profiles. Compounds contain-
ing 4-thiazolidinone moiety possessing an assortment of pharmacological activities such
as antibacterial,[1] anticancer,[2] antitubercular,[3] antioxidant,[4] anti-inflammatory,[5]
COX-1 inhibitor,[6] anti HIV,[7] and anti-histaminic agents.[8] Further, the presence of
CONTACT Manisha R. Bhosle
d.manisha11@gmail.com
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad, Maharashtra, 431004, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
M. R. BHOSLE ET AL.
O
OH
R
O
O
N
O
S
S
HN
O
O
H
N
NH
N
N
N
N
N
O
H
N
S
O
O
O
S
S
N
S
O
O
(D)
O
O2N
(C)
(B)
(A)
O
N
R
N
N
S
H
N
O
N
HN
N
S
O
HN
F3C
O
O
S
(F)
(G)
O
(E)
HOOC
Figure 1. 4-Thiazolidinone and thiazole containing bioactive molecules.
the N-C-S linkage in the thiazolidinone is also responsible for the treatment of diabetic
neuropathy, an aldose reductase inhibitor.[9] These have given the 4-thiazolidinone
framework the status of a privileged pharmacophore that makes the functionalized thia-
zolidinones highly sought for compounds for medicinal chemists toward the generation
of new therapeutic leads. Figure 1 shows molecules having 4-thiazolidinone as
pharmacophore.[10]
The thiazoles are also important pharmacophores found in a wide variety of bioactive
molecules and natural products (Fig. 1).[11] Thiazole derivatives are associated with a
broad spectrum of biological properties, including antitumor,[12] antiparasitic,[13] anti-
fungal,[14] antimicrobial,[15] antiproliferative,[16] antihypertension,[17] anti-inflamma-
tion,[18] oxidase inhibitors, and free radical scavengers.[19] Some novel thiazole
derivatives[20] especially BILS 179 BS8 were reported to exhibit a high antiviral activity
against hepatitis C virus (HCV) and HSV, respectively. Considering the above signifi-
cance of both molecules we decided to combine 4-thiazolidinone and thiazole in one
molecular framework to obtain new hybrids, thiazolyl-4-thiazolidinones.
The relevance of these structural motifs has constituted the focus of many investigations
regarding improved strategies for their synthesis. In the literature, several campaigns for
the synthesis of thiazolidinones are known either via multicomponent tandem reaction or
two-step process.[21] However, the most commonly used protocol is multicomponent tan-
dem reaction between a primary amine, aldehyde, and thioglycolic acid. There are reports
of acceleration of the above cyclocondensation using catalysts and coupling agents such as
DCC,[22] HBTU[23] or metal Lewis acid catalysts,[24] solid acid catalysts,[25] activated fly
ash,[26] ionic liquids,[27] silica gel[28] and nano-Fe3O4@SiO2.[29] However, some of these
methods suffer from at least one of the following disadvantages: longer reaction time, cor-
rosive nature, hazardous reaction conditions, tedious work-up procedures, unsatisfactory
yields, and use of non-recyclable reagents. Thus, a convenient, versatile, rapid and high

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3
yielding synthetic method is needed to fulfill the timely supply of the designed molecules
and enrichment of medicinal chemists’ tool box.
Finding novel synthetic procedures for a variety of attractive compounds that can be
considered as pharmaceutics has been investigated over the last decades. Catalysis plays a
central role in chemical processes and lies at the heart of countless chemical transforma-
tions, from academic research at laboratories level to the chemical industry level. By using
catalytic systems, one can reduce the temperature of a chemical reaction, reduce reagent-
based waste, and enhance the yield of a transformation that potentially avoids the
unwanted side reactions leading to a green technology.[30] The introduction of new meth-
odologies in recent years based on environmentally friendly conditions using the efficient
and reusable catalyst as well as water-mediated procedures has gained significant attention
among the researchers.[31] Excipients are widely used as drug delivery systems and bio-
pharmaceuticals. However, when they are introduced into organic synthesis they act as a
catalyst and some as a reaction medium.[32] For decades, various excipients, including chi-
tosan,[33] meglumine,[34] PEG-400[35] have been developed and reported as catalyst and
medium. Tromethamine (Tris(hydroxymethyl) aminomethane) is excipient used as organo-
catalyst by Desai and Kim et al. for the efficient synthesis of pyran-annulated heterocycles
and b-phosphonomalonates respectively.[36] Tromethamine, which contains an amino and
three alcoholic groups, it is physiologically inert, biodegradable, noncorrosive, and is avail-
able commercially at extremely low cost.[37]
As part of our continuing efforts to synthesize new heterocyclic scaffolds in an
environmentally benign fashion,[38] we have applied developing organocatalysis in
combination with water for the efficient preparation of the desired hybrids, thiazolyl-4-
thiazolidinones. Considering the use of excepients to be an effective catalyst for various
transformations, herein we report tromethamine in water as green catalytic system
which makes the synthetic process more applicable. To the best of our knowledge, this
type of catalytic system has not been documented for the present transformation.
Result and discussion
In the present work initially, to get 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde (1) as
required precursor, we performed the reaction sequence starting from thiobenzamide.[39]
Thiobenzamide cyclocondensed with 1,3-dicloro acetone in ethanol at 80 ꢀC to obtain
chloromethyl thiazole. Chloromethyl thiazole further condensed with 4-hydroxy benzalde-
hyde in the presence of K2CO3/DMF at room temperature to get desired starting 4-((2-
Phenylthiazol-4-yl)methoxy)benzaldehyde (1) in excellent yield.
Water is a very attractive solvent for a number of efficient organic reactions at differ-
ent temperature. The use of water in multicomponent reactions offers significant envir-
onment advantages and has attracted a great deal of interest in recent years.[40] Water
promotes or accelerates an excellent supporting medium with numerous advantages
including the ease of product isolation, non-toxicity, non-flammability, high heat cap-
acity and redox stability. Many organic transformations were known to promote by
water.[41] Therefore, We commenced our investigation with a reaction using an equimo-
lar ratio of freshly prepared 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde (1), aniline
(2a) and thioglycolic acid (3) as model substrates in water (Scheme 1). To solublize the

4
M. R. BHOSLE ET AL.
Scheme 1. 2-(4-((2-Phenylthiazol-4-yl)methoxy)phenyl)-3-phenylthiazolidin-4-one (3a).
Table 1. Formation of 2-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-3-phenylthiazolidin-4-one (3a) using
different catalyst in aqueous medium.
Entry
Catalyst/Solvent
Catalyst Loading (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
H2O
—
20
20
20
20
20
20
20
15
1
1
1
1
1
1
1
1
1
1
1
1
1
27
64
59
48
45
76
42
51
CTAB/H2O
TTAB/H2O
p-TSA/H2O
a-Cyclodextrin/H2O
b-Cyclodextrin/H2O
c-Cyclodextrin/H2O
Taurine/H2O
Tromethamine/H2O
9
10, 20, 30, 40
43, 71, 82and 83
32, 56, 81, 83
10
11
12
13
14
Tromethamine/H2O (rt, 60, 80, 100 ꢀC)
Tromethamine/EtOH
Tromethamine/EtOH:H2O (1:1)
Tromethamine/MeOH
Tromethamine/CH3CN
20
20
20
20
20
79
80
74
51
aReaction conditions: 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde (1) (4 mmol), aniline (4 mmol), thioglycolic acid
(8 mmol), water (15 mL), 80 ꢀC.
bIsolated yield.
organic reactants in water various catalysts such as CTAB, TTAB, p-TSA,
b-Cyclodextrin, Taurine, and Tromethamine were screened for the model reaction
(Table 1, entries 1–9) at 80 ꢀC for 1 h. Amongst them, tromethamine were found to be
an excellent catalyst, furnishing the product in excellent yield of 82% (Table 1, entry 9).
In the absence of catalyst, the one-pot multicomponent cyclocondensation at reflux
temperature in water did not exhibit similar reaction condensations (Table 1, entry 1).
To derive the superlative reaction parameters such as the amount of the catalyst required
and temperature, and the influence of the solvent for the tromethamine catalyzed 4-thiazoli-
dinone formation, the model reaction (Scheme 1) was performed under different variations
of these parameters. The use of 30 mol% of load of catalyst tromethmine afforded the com-
pound 3a in 82% yields (Table 1, entry 9) within 1 h under aqueous conditions. However,
an increase in the amount of catalyst did not result in any improvement in the yield of the
product. Temperature plays an important role to carry out the cyclocondensation.
Consequently, the effect of temperature on the test reaction was investigated by carrying
out the reaction at rt, 60, 80, and 100 ꢀC in water (Table 1, entry 10). It was observed that
at a temperature lower than 80 ꢀC, the reaction did not proceed efficiently and, at higher
temperatures, only a marginal increase in the product yield was observed. Thus, 80 ꢀC was
chosen as the optimum reaction temperature for the synthesis of 4-thiazolidinones.
Subsequently, different solvents were screened to test the efficiency of the catalyst in
different reaction media, and the results are presented in Table 1. The polar protic sol-
vents (EtOH, EtOH:H2O (1:1), MeOH), afforded higher yields 79, 80, 74% than the
polar aprotic (CH3CN) ones and water showed superiority among the different polar
solvents investigated (Table 1, entry 11–14).

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5
82
81.5
81
80.5
80
Yield (%)
79.5
79
Fresh
Run I
Run II
Run III
No. of Recycles
Figure 2. Reuse of tromethamine/water and its effect on yield (%).
Scheme 2. Synthesis of 3-(substituted phenyl)-2-(4-((2-phenylthiazol-4-yl)methoxy)phenyl) thiazolidin-4-
ones (3a-l).
The reusability of catalysts is valuable advantages in modern catalysis research and
commercial uses as well as in green chemistry. In this respect, the recovery and reus-
ability of tromethamine were investigated for the model reaction. Tromethamine is
completely soluble in reaction media water therefore its isolation and reuse is tedious
and expensive.[36a] In this circumstance, we authenticated reusability of the reaction
medium. Consequently, the model reaction was performed. The resultant product was
isolated by extraction, and the filtrate obtained was reused for the synthesis of 3a. The
reaction media and tromethamine was studied for three successive cycles, showing with-
out an appreciable reduction in catalytic activity. Only a slight decrease in the yield of
the desired product, 3a, was noticed (Fig. 2).
Inspired by these observations and to generalize the synthetic procedure, a variety of
electronically divergent aromatic amines were treated with 4-((2-Phenylthiazol-4-yl)me-
thoxy)benzaldehyde and mercaptoacetic acid in presence of tromethamine in water
(Scheme 2). Aromatic amines with several functionalities such as Cl, OH, CH3, OCH3
and NO2 were found to be compatible under the optimized reaction condition
(Table 2).
After our initial success, the general applicability of the newly developed protocol is dem-
onstrated through the reaction of various aryl aldehydes reacted elegantly with substituted
anilines and thioglycolic acid to form the corresponding 1,3-disubstituted-4-thiazolidinones
in excellent yields (Scheme 3). The reactions proceeded well with electron donating
and withdrawing substituted aromatic aldehydes, as well as different variations of the
amines affording the respective thiazolidinone in very good to excellent (84–93%)
yields (Table 3).

6
M. R. BHOSLE ET AL.
Table 2. Substrate scope of the present tandem MCR for synthesis of 3-(substituted phenyl)-2-(4-
((2-phenylthiazol-4-yl)methoxy) phenyl) thiazolidin-4-ones (3a–l).
S
NH2
O
SH
O
HOOC
N
S
N
O
N
O
+
S
THAM, H 2O, Reflux
R
R
Yield
(%)
Sr. No.
Aniline
Compound
1
82
79
3a
2
3
4
5
6
81
89
80
76
(continued)

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7
7
8
86
80
9
86
89
82
10
11
12
87
aReaction Conditions: 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde (4) (4 mmol), substituted amines (2a-l) (4 mmol),
Thioglycolic acid (8 mmol), Tromethamine (30 mol%), Water (15 mL) stirred at 80 ꢀC.
bIsolated yield.
Scheme 3. Synthesis of 1,3-disubstituted-4-thiazolidinones (5a–l).

8
M. R. BHOSLE ET AL.
Table 3. Substrate scope for synthesis 2,3-disubstituted 4-thiazolidinones (5a–l).
Sr. No.
R’
R
Product
Yield (%)
1
H
H
H
93
2
4-CH3
89
3
4
4-OCH3
4-OH
H
H
86
87
5
6
4-Cl
H
H
90
86
4-NO2
7
8
9
H
4-CH3
4-CH3
4-CH3
94
84
87
4-CH3
4-OCH3
(continued)

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9
10
4-OH
4-CH3
93
11
12
4-Cl
4-CH3
4-CH3
93
85
4-NO2
aReaction conditions: Substituted benzaldehydes (4a-f) (4 mmol), substituted amines (2a-b) (4 mmol), thio-
glycolic acid (8 mmol), tromethamine (30 mol%), water (15 mL) stirred at 80 ꢀC.
bIsolated yield.
cMelting points are in good agreement with those reported in the literature.[38a,42]
.
Plausible mechanism of reaction
It is known that tromethamine contains an amino and three alcoholic groups and are
inert. Amino hydrogen of tromethamine favors interaction with an oxygen atom of the
carbonyl group of the aldehyde, followed by nucleophilic attack of substituted amines,
leading to the formation of an imine intermediate (A). Then, free hydroxyl group inter-
act with the protons of thioglycolic acid and the sulfur anions of thioglycolic acid attack
the activated imine group of the intermediate (A), affording the intermediate (B). Next,
the tromethamine again activates the intermediate (B), followed by removal of water,
resulting in the final desired 4-thiazolidinones (Scheme 4).
Experimental
General: All the chemicals used were of laboratory grade. Melting points of all the syn-
1
thesized compounds were determined in open capillary tubes and are uncorrected. H
NMR spectra were recorded with a Bruker Avance 400 spectrometer operating at
400 MHz using DMSO solvent and tetramethylsilane (TMS) as the internal standard
and chemical shift in d ppm. Mass spectra were recorded on a Sciex, Model; API 3000
LCMS/MS Instrument. The elemental analysis was done on Thermofisher EA1112 series
CHNS Elemental Analyzer. The purity of each compound was checked by TLC using
silica-gel, 60F254 aluminum sheets as adsorbent and visualization was accomplished by
iodine/ultraviolet light.
General procedure for the synthesis of 3-(substituted phenyl)-2-(4-((2-
phenylthiazol-4-yl)methoxy) phenyl) thiazolidin-4-ones (3a-l)
The mixture of 4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde (1) (4 mmol) and substituted
anilines (2a-l) (4.1 mmol) in water (20 mL) containing tris-hydroxymethylaminomethane

10
M. R. BHOSLE ET AL.
Scheme 4. Plausible mechanism for the synthesis of 4-thiazolidinones.
(Tromethamine) (30 mol%) was stirred at 80 ꢀC for 15 min. Then thioglycolic acid (8 mmol)
was added and stirred at 80 ꢀC. Progress of the reaction was monitored by thin layer chro-
matography ethyl acetate:hexane (3:7) as solvent. After 45 min. of stirring reaction mixture
was cooled at room temperature, saturated sodium bicarbonate was added till gate pink
color, to remove thioglycolic acid. Sticky compound was extracted with ethyl acetate and
evaporated organic layer under reduced pressure. Thus obtained solid was filtered, dried
and purified by crystallization using ethanol as solvent.
Recycling of reaction media
The mixture of 4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde (1) (8 mmol) and anilines (2a)
(8 mmol) in water (40 mL) containing tris-hydroxymethylaminomethane (Tromethamine)
(30 mol%) was stirred at 80 ꢀC for 15 min. Then thioglycolic acid (16 mmol) was added
and stirred at 80 ꢀC. Progress of the reaction was monitored by thin layer chromatography
ethyl acetate:hexane (3:7) as solvent. After 45 min of stirring reaction mixture was cooled
at room temperature. Sticky compound was extracted with ethyl acetate and evaporated
organic layer under reduced pressure. The aqueous layer having soluble tromethamine was
further reused for next cycle.

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11
Spectral analysis of compounds
3-Phenyl-2-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)thiazolidin-4-one (3a)
Yellow solid, yield 82%, melting point 146–148 ꢀC. IR (ATR, t cmꢁ1) characteristic
absorptions: 3250, 3193, 3076, 2888, 2343, 1641, 1480, 1490, 1325, 1171, 947, 747.
1H NMR (400 MHz, DMSO dppm):4.37–4.43 (dd, 2 H, CH2), 5.20 (s, 2 H, CH2), 6.08
(s, 1 H, CH), 7.38–7.51 (m, 2 H, Ar-H), 7.55–7.70 (m, 4 H, Ar-H), 7.77–7.96 (m, 4 H, Ar-H),
8.04–8.46 (m, 5 H, Ar-H). MS (Scanning mode, ESIþ) m/z: 445.5 (Mþ). Elemental Anal.
calcd. for C25H20N2O2S2: C: 67.54; H: 4.53; N: 6.30; S: 14.43; Found: C: 67.53; H: 4.55;
N: 6.37; S: 14.41.
General procedure for the synthesis of 1,3-disubstituted-4-thiazolidinones (5a-l)
The mixture of substituted aldehydes (4a-f) (4 mmol) and substituted anilines (2a-b)
(4.1 mmol) in water (20 mL) containing tris-hydroxymethylaminomethane (Tromethamine)
(30 mol%) was stirred at 80 ꢀC for 15 min. Then thioglycolic acid (8 mmol) was added and
stirred at 80 ꢀC. Progress of the reaction was monitored by thin layer chromatography
ethyl acetate:hexane (3:7) as solvent. After 45 min. of stirring reaction mixture was cooled
at room temperature, saturated sodium bicarbonate was added till gate pink color, to
remove thioglycolic acid. Sticky compound was extracted with ethyl acetate and evaporated
organic layer under reduced pressure. Thus obtained solid was filtered, dried and purified
by crystallization using ethanol as solvent.
1
Synthesized compounds characterized by IR, H NMR and Melting points are in
good agreement with those reported in the literature.38a,42
3-Phenyl-2-(4-tolyl)thiazolidin-4-one (5b)
White solid, Yield 89%. Melting point 103–105 ꢀC. IR (ATR, t cmꢁ1) characteristic
1
absorptions: 3202, 2975, 2827, 2357, 1725, 1453, 1149, 1008, 857, 759. H NMR (400 MHz,
DMSO dppm): 2.26 (s, 3 H, CH3), 3.83–4.02 (dd, 2 H, CH2), 5.99 (s, 1 H, CH), 7.01–7.29
(m, 9 H, Ar-H). MS (Scanning mode, ESIþ): m/z (% intensity): 270 (Mþ). Elemental Anal.
calcd. For C16H15NOS: C: 71.34; H: 5.61; N: 5.20; S: 11.90; Found: C: 71.35; H: 5.60;
N: 5.25; S: 11.93.
Conclusion
A tromethamine in water was used as an efficient and green catalytic system for the
synthesis of new thiazolyl 4-thiazolidinone and known substituted-4-thiazolidinone via
a one-pot, three-component reaction of an thiazolylmethoxy phenyl/aromatic carboxal-
dehyde, substituted amines and thioglycolic acid in good to excellent yields at 80 ꢀC in
water. The reaction system was considerably affected by catalyst loading, temperature
and solvent. The advantages of using of tromethamine as the catalyst are it is environ-
mentally friendly, low cost, commercially available, easy to separate from the reaction
mixture, and has high reusability. Use of tromethamine catalyst results in acceptable

12
M. R. BHOSLE ET AL.
reaction time, high yields and high purities of the obtained products. All of these points
are in full compliance with the requirements of green chemistry.
Supporting information (SI)
1
Full experimental detail, IR, H and 13C NMR spectra, this material can be found via
the “Supplementary Content” section of this article’s webpage.’
Acknowledgments
The authors are thankful to Professor Ramrao A. Mane for his invaluable discussions and guid-
ance. The authors are also thankful to Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad and Central Drug Research Institute (CDRI), Lucknow for
providing necessary facilities and spectral analysis respectively.
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